Switching Drugs Tricky for Stroke in AF

Action Points

Note that this post-hoc analysis of a randomized controlled trial revealed no increased thrombotic risk after temporary cessation of rivaroxaban versus warfarin.

Be aware that during the conversion to open-label warfarin, rivaroxaban-treated patients sufferred a higher rate of both bleeding and thrombosis.

Stopping rivaroxaban (Xarelto) doesn't appear to be worse for atrial fibrillation patients than stopping warfarin, but switching from rivaroxaban to warfarin can be problematic, a ROCKET AF trial analysis suggested.

Temporary interruption or early permanent discontinuation of the new drug didn't boost stroke and other thromboembolic events compared with the same changes in warfarin treatment, Manesh R. Patel, MD, of the Duke Clinical Research Institute, and colleagues found.

But the transition to open-label anticoagulation after the end of the trial went worse for the rivaroxaban group than those who stayed on warfarin, with 3.72-fold more strokes in the 3 to 30 days after the end of study drug dosing, they reported in the Feb. 12 issue of the Journal of the American College of Cardiology.

The culprit appeared to be a gap in antithrombotic coverage during the switch, with 51% of the rivaroxaban group not reaching therapeutic levels of warfarin within 30 days, as had been presented by the group in a webinar last year.

The more detailed analysis may help ease fears of a prothrombotic rebound effect of rivaroxaban, Matthew R. Reynolds, MD, MSC, of the Harvard Clinical Research Institute and VA Healthcare System in Boston, noted in an accompanying editorial.

However, while the antithrombotic gap explanation "is fairly persuasive, the evidence that the post-study excess stroke risk in rivaroxaban patients was the result of inadequate vitamin K antagonist therapy remains somewhat circumstantial," he wrote.

International normalized ratio (INR) values weren't collected as carefully after the trial, nor was there any data on bridging with unfractionated or low-molecular-weight heparin.

Also, a counterintuitive 3.62-fold rise in bleeding risk occurred during the post-trial period in the rivaroxaban group compared with the warfarin group (7.3 versus 2.0 events per 100 patient-years, P=0.003).

"What is clearest from this important subanalysis of the ROCKET AF trial is that bad things will happen to high-risk AF patients if they are left untreated with effective anticoagulant therapy for sustained periods -- and that in a population as large as this one, it does not take much time for those events to begin to accumulate," Reynolds wrote.

The researchers agreed that the message for clinicians is to ensure timely anticoagulation coverage during transition from rivaroxaban to warfarin.

"Whether bridging anticoagulation will produce net clinical benefit is unclear, but it seems wise to minimize the period of discontinuation," they wrote.

Temporary interruptions in dosing in the trial -- typically due to surgical and other invasive procedures -- averaged 6 days.

Stroke and non-CNS embolism occurred at a similar rate within 30 days of such periods with rivaroxaban and warfarin, at 6.20 versus 5.05 per 100 patient-years (hazard ratio 1.28, P=0.62).

The researchers noted the small number of events in this comparison -- nine and eight, respectively -- across the 14,624-patient trial.

Nevertheless, "Stated another way, even with short temporary interruptions, the protection from anticoagulant therapy for AF is lost, and the baseline patient risk becomes evident when observed over several thousand interruptions," they wrote.

Likewise, after early permanent study drug discontinuation, the difference in 30-day rate of stroke and other embolic events between groups wasn't significant, at 25.60 per 100 patient-years in the rivaroxaban group and 23.28 in the warfarin group (HR 1.10, P=0.66).

The high event rate reflected the high-risk population who couldn't tolerate anticoagulation due to adverse events (39%) or who had a suspected on-drug stroke or other primary endpoint event (13%), the investigators noted.

After the end-of-study transition to open-label therapy, 22 strokes or non-CNS embolic events occurred in the rivaroxaban group versus six in the warfarin group, for a rate of 6.42 versus 1.73 per 100 patient-years (P=0.0044).

The same patterns were seen for the three time periods when adding together stroke, non-CNS embolism, myocardial infarction, and vascular death.

Major bleeds didn't differ significantly between groups except in the post-study transition period (7.29 for rivaroxaban versus 2.01 for warfarin per 100-patient years, P<0.0026).

"Further research is needed to understand how to manage these patients best," the researchers concluded.

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